DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“AN IMPROVED PROCESS FOR THE PREPARATION OF BEMPEDOIC ACID”

APPLICANT (S)

a) NAME : METROCHEM API PVT LTD, R&D Centre
b) NATIONALITY : India
c) ADDRESS : Plot No. 298/P, Phase-I, Pipeline road
IDA Jeedimetla, Hyderabad- 500055
Telangana, India

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of bempedoic acid of formula I.
BACKGROUND OF THE INVENTION:
Bempedoic acid is an oral, nonstatin therapy designed to primarily work in the liver to inhibit cholesterol biosynthesis. Bempedoic acid blocks an enzyme in the liver called adenosine triphosphate citrate lyase, which is involved in making cholesterol. Bempedoic acid as a monotherapy or in combination with Ezetimibe was approved for the treatment of hypercholesterolemia and sold under the brand name Nexletol and Nexlizet respectively.

Bempedoic acid is chemically known as 8-hydroxy-2,2,14,14-tetramethyl pentadecanedioic acid and is represented by the following structural formula I

Formula I
Bempedoic acid and process for its preparation was first disclosed in US7335799 (the “US’799 patent”). The disclosed process involves reaction of 1,5-dibromopentane (1) with ethyl isobutyrate (2) in presence of lithiumdiisoproylamide in tetrahydrofuran to give ethyl 7-bromo-2,2-dimethylheptanoate (3), which is dimerized with p-toluenesulfonyl methyl isocyanide in the presence of sodium hydride and Bu4NI in dimethylsulfoxide under argon atmosphere to give diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate (4); hydrolyzing the compound (4) with HCl in methyelenchloride to give crude keto compound (5), which is further purified using column chromatography, and then hydrolyzed with aqueous potassium hydroxide in ethanol under reflux conditions to give compound (6). Finally, reducing the compound (6) with sodium borohydride in methanol to give bempedoic acid. The said process is schematically represented by the following scheme

The process disclosed in US’799 patents involves number of drawbacks such as intermediate and final compounds obtained in very low yields and purity; the final compound bempedoic acid is obtained only with 83.8% purity in on viscous oil form; involves higher volume of hydrochloric acid in for hydrolysis of compound (4) which leads to higher amount of impurities and results in low yield; involves use of chromatographic technique for purification of compound (5) to remove p-toluene sulfonic acid by product, which is not feasible in commercial scale; very excess amount of sodium borohydride required for reduction of compound (6) due to prior hydrolysis of ester group. The said process involves high amount of reagents and chromatographic technique for purification, make its tedious, higher cost of product and commercially not viable.

Hence there is a need in the art for an improved process for the preparation of bempedoic acid, which is cost effective, avoids column chromatography, higher amount of reagents/acid and tedious workup as in prior art.

SUMMARY OF THE INVENTION:
Accordingly, the present invention provides an improved process for the preparation of bempedoic acid of formula I, which is simple, cost effective and industrially feasible.
In one embodiment, the present invention provides an improved process for the preparation of bempedoic acid of formula I, which comprises
a) reacting 1,5-dibromopentane of formula II with alkyl isobutyrate compound of formula III in presence of a base in a suitable solvent to provide alkyl 7-bromo-2,2-dimethylheptanoate of formula IV,
b) reacting the compound of formula IV with p-toluene sulfonyl methyl isocyanide in presence of a base and a catalyst in a suitable solvent to provide compound of formula V,
c) reacting the compound of formula V with a suitable acid in a suitable solvent to provide keto compound of formula VI,
d) reducing the keto compound of formula VI with a suitable reducing agent in presence of a base in a suitable solvent to provide the compound of formula VII,
e) hydrolyzing the compound of formula VII with a suitable base or acid to provide the bempedoic acid of formula I, and
f) optionally purifying the bempedoic acid of formula I from a suitable solvent.

In another embodiment, the present invention provides a process for the preparation of bempedoic acid, which comprise of reducing the keto compound of formula VI with a suitable reducing agent, followed by treating with a suitable base to provide bempedoic acid of formula I.

In another embodiment, the present invention provides a process for the preparation of bempedoic acid of formula I, which comprises
a) reacting the compound of formula IV with p-toluene sulfonyl methyl isocyanide in presence of a base and a catalyst in a suitable solvent to provide compound of formula V,
b) reacting the compound of formula V with a suitable acid in a suitable solvent to provide keto compound of formula VI,
c) reducing the keto compound of formula VI with a suitable reducing agent in presence of a base in a suitable solvent to provide the compound of formula VII,
d) hydrolyzing the compound of formula VII with a suitable base or acid to provide the bempedoic acid of formula I;
wherein the compound of formula V, compound of formula VI and compound of formula VII is not isolated and carried out as a one-pot process.

In another embodiment, the present invention provides a process for the preparation of bempedoic acid, which comprise of reacting the compound of formula V with a suitable acid to provide keto compound of formula VI, wherein the said reaction is carried out in presence of aromatic hydrocarbon solvent.

In another embodiment, the present invention provides a process for the purification of bempedoic acid compound of formula I, which comprise of crystallizing bempedoic acid from a suitable solvents or mixtures thereof.

In another embodiment, the present invention provides crystalline form of bempedoic acid characterized by powder X-ray diffraction pattern shown in the Figure 1.

In another embodiment, the present invention provides crystalline form of bempedoic acid characterized by its PXRD pattern having one or more peaks at 5.14, 10.30, 15.46, 17.24, 17.52, 17.89, 18.21, 18.69, 19.46, 20.33, 20.67, 21.78, 22.55, 23.50 and 27.49 ± 0.2 degrees 2?.

In another embodiment, the present invention provides a process for the preparation of crystalline bempedoic acid of formula 1, which comprise of crystallizing bempedoic from a suitable solvent selected from ketone, ester, nitrile, ether solvents or mixtures thereof.

In another embodiment, the present invention provides pharmaceutical composition comprising crystalline bempedoic acid characterized by PXRD pattern as shown in Figure 1 or bempedoic acid prepared according to the present invention and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS:
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.
Figure 1 is the characteristic powder X-ray diffraction (XRD) pattern of bempedoic acid obtained as per example 5 of the present invention.

DETAILED DESCRIPTION OF THE INVENTION:
Unless otherwise specified the term “alkyl” used herein the specification refers to C1-C6 alkyl and is selected from but not limited to, methyl, ethyl, propyl, isopropyl, butyl and the like.

Unless otherwise specified, as used herein the specification, the term “ethers” refers to tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tertiary butyl ether, cyclopentyl methyl ether and the like; the term “aliphatic hydrocarbons” refers to heptanes, hexane, cyclohexane, cyclopentane, methylcylohexane and the like; the term “aromatic hydrocarbons” refers to toluene, xylene, benzene and the like; the term “amides” refers to formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and the like; the term “sulfoxides” refers to dimethylsulfoxide and the like; the term “ketones” refers to acetone, methylethylketone, methylisobutylketone, diethylketone and the like; the term “alcohols” refers to methanol, ethanol, isopropanol, butanol and the like; the term “nitriles” refers to acetonitrile, propionitrile, butyronitrile and the like.

The present invention provides an improved process for the preparation of bempedoic acid of formula I.
In one embodiment, the present invention provides an improved process for the preparation of bempedoic acid of formula I,

Formula I
which comprises
a) reacting 1,5-dibromopentane of formula II

Formula II
with alkyl isobutyrate compound of formula III

Formula III
wherein R is C1-C6 alkyl; in presence of a base in a suitable solvent to provide alkyl 7-bromo-2,2-dimethylheptanoate of formula IV, wherein R is C1-C6 alkyl;

Formula IV
b) reacting the compound of formula IV with p-toluene sulfonyl methyl isocyanide in presence of a base and a catalyst in a suitable solvent to provide compound of formula V, wherein R is C1-C6 alkyl;

Formula V
c) reacting the compound of formula V with a suitable acid in a suitable solvent to provide keto compound of formula VI, wherein R is C1-C6 alkyl;

Formula VI
d) reducing the keto compound of formula VI with a suitable reducing agent in presence of a base in a suitable solvent to provide the compound of formula VII, wherein R is C1-C6 alkyl,

Formula VII
e) hydrolyzing the compound of formula VII with a suitable base or acid in a suitable solvent to provide the bempedoic acid of formula I; and
f) optionally purifying the bempedoic acid of formula I from a suitable solvent.

The starting materials used in the present invention i.e., 1,5-dibromopentane of formula II and alkyl isobutyrate of formula III was known in the art and are commercially available.

The step a) of the forgoing process involves reacting the 1,5-dibromopentane of formula II with alkyl isobutyrate of formula III, wherein R is C1 to C6 alkyl selected from methyl, ethyl, isopropyl and butyl; preferably, ethyl; in presence of a base in a suitable solvent to provide alkyl 7-bromo-2,2-dimethylheptanoate of formula IV; wherein the base used herein is selected from lithium diisopropylamide, lithium diethylamide, lithium dicyclohexylamide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide and n-butyl lithium; and a suitable solvent used herein is selected from ethers, aliphatic hydrocarbons or mixtures thereof; preferably, the solvent is ethers, and most preferably tetrahydrofuran.

The step b) of the forgoing process involves reacting the compound of formula IV, wherein R is selected from C1 to C6 alkyl, preferably, ethyl; with p-toluene sulfonyl methyl isocyanide in presence of a base and a catalyst in a suitable solvent to provide compound of formula V; wherein the base is selected from alkali metal hydrides such as sodium hydride, potassium hydride or lithium hydride; alkali metal amides such as sodium amide, potassium amide or lithium amide; alkoxides such sodium methoxide, potassium methoxide, sodium t-butoxide and the like; preferably the base is alkali metal hydride; and more preferably sodium hydride; the catalyst used herein is selected from tetraalkylammonium halide, benzyltrialkylammonium halide, dibenzyl dialkyl ammonium halide and the like; preferably the catalyst is tetraalkylammonium halide; more preferably, tetrabutylammonium iodide; and the solvent is selected from aromatic hydrocarbons, amides, sulfoxides, ethers, aliphatic hydrocarbons, ketones, or mixtures thereof; preferably aromatic hydrocarbons and amides; and more preferably dimethylformamide and toluene.

In an embodiment, the compound of formula V in step b) is not isolated and proceeds to next step in the form of organic layer without any further purification.

The step c) of the forgoing process involves reaction of compound of formula V, wherein R is selected from C1 to C6 alkyl, preferably, ethyl; with a suitable in a suitable solvent to provide keto compound of formula VI; wherein the suitable acid is selected from acetic acid, sulphuric acid and hydrochloric acid; preferably hydrochloric acid; and the suitable solvent is selected from hydrocarbons such as toluene, xylene, benzene and the like or mixtures thereof; preferably, the solvent is toluene.

The step c) reaction is suitably carried out at a temperature of about 0-20°C and preferably about 0-5°C, for a suitable period of time to complete the reaction; preferably 1-3 hrs.

In an embodiment, the compound of formula VI in step c) is not isolated and proceeds to next step in the form of organic layer without any further purification.

The process reported in US’739 involves purification of compound of formula VI by column chromatography in order to remove the by-products; further involves use of higher amount of hydrochloric acid (14 equivalents) for hydrolysis of formula VI which leads to higher amount of impurities and lower the yield of final product. In contrast, the present invention involves use of 4.5 equivalents of hydrochloric acid and thereby reduces unwanted impurity formation; further utilizing aromatic hydrocarbon solvent, such as toluene as a solvent, in which by-product is not soluble and thereby easily removing the by-product after reaction completion by simple filtration and avoids column purification of prior art.

In an embodiment, the present invention provides use of aromatic hydrocarbon solvent for the reaction of compound of formula V with a suitable acid to provide keto compound of formula VI.

The step d) of the forgoing process involves reduction of the keto compound of formula VI, wherein R is selected from C1 to C6 alkyl, preferably, ethyl; with a suitable reducing agent in presence of a base in a suitable solvent to provide the compound of formula VII, wherein the suitable reducing agent is selected from sodium borohydride, sodium triacetoxyborohydride, sodiumcyano borohydride, potassium borohydride and the like; and a base is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal carbonates such sodium carbonate, potassium carbonate and the like; and a suitable solvent is selected from water, alcohols, aromatic hydrocarbons, ethers and mixtures thereof; preferably alcohol and aromatic hydrocarbons; more preferably methanol or ethanol and toluene.
The step d) reaction is suitably carried out at a temperature of about 20°C to about 40°C, preferably at about 20-30°C, for a suitable period of time to complete the reaction, preferably for 1-2 hrs.

In an embodiment, the compound of formula VII of step d) is not isolated from the reaction mass and proceeds to next to steps without any purification.

In another embodiment, the present invention provides a process for the preparation of bempedoic acid, which comprise of reducing the keto compound of formula VI with a suitable reducing agent, followed by treating the obtained compound of formula VII present in reaction mass with a suitable base to provide bempedoic acid of formula I.

The step e) of the forgoing process involves hydrolysis of compound of formula VII, wherein R is selected from C1 to C6 alkyl, preferably, ethyl; with a suitable base or acid in a suitable solvent to provide bempedoic acid of formula I; wherein the suitable base is selected from alkali metal hydroxides such sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkali metal alkoxides such sodium methoxide, potassium methoxide, sodium t-butoxide and the like; and a suitable acid used herein is selected from aqueous hydrochloric acid or sulphuric acid; preferably, hydrolysis carried out in presence of alkali metal hydroxides such as sodium hydroxide.

The step e) of the forgoing process suitably carried out at a temperature of about 45°C to about 65°C, preferably at about 50-60°C, for a suitable time to complete the reaction, preferably for 5-6 hrs.

The compound of formula I obtained in step e) is isolated from the reaction mass by the methods known in the art, for example, filtration and the obtained compound is further dried at a suitable temperature.
The step f) of the forgoing process involves purification of bempedoic acid compound of formula I by crystallizing from a suitable solvent; wherein the suitable solvent is selected from ethers, nitriles, ketones, esters, alcohols, water and mixtures thereof; preferably the solvent is ketones and esters; more preferably acetone and ethyl acetate.

In another embodiment, the present invention provides crystalline form of bempedoic acid characterized by powder X-ray diffraction pattern shown in the Figure 1.

In another embodiment, the present invention provides crystalline form of bempedoic acid characterized by its powder X-ray diffraction having one or more peaks at 5.14, 10.30, 15.46, 17.24, 17.52, 17.89, 18.21, 18.69, 19.46, 20.33, 20.67, 21.78, 22.55, 23.50 and 27.49 ± 0.2 degrees 2?.

In another embodiment, the present invention provides a process for the preparation of crystalline bempedoic acid of formula 1, which comprise of crystallizing bempedoic from a suitable solvent selected from nitriles, ketones, ethers, esters and mixtures thereof; preferably from mixture of acetone and ethyl acetate or acetonitrile.

In another embodiment, the present invention provides a process for the purification of bempedoic acid compound of formula I, which comprise of crystallizing bempedoic acid from a suitable solvents or mixtures thereof.

The suitable solvent herein used for purification of formula I is selected from ethers, nitriles, ketones, esters, alcohols, water and mixtures thereof. Preferably the compound of formula I crystallized using mixture of ketones and esters; more preferably ethyl acetate and acetone. The said purification carried out at a temperature of about 25°C to about reflux temperature of solvent.

In another embodiment, the present invention provides pharmaceutical composition comprising crystalline bempedoic acid characterized by Figure 1 or bempedoic acid prepared according to the present invention and at least one pharmaceutically acceptable excipient.

Examples:
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Example 1:
Preparation of ethyl 7-bromo-2,2-dimethylheptanoate:
Lithiumdiisopropylamide (5 L) was added to a mixture of 1,5-dibromo pentane (2.38 Kg), ethyl isobutyrate (1 Kg) and tetrahydrofuran (5 L) at 0-5°C under nitrogen atmosphere. The reaction mass was heated to 25-35°C and stirred at the same temperature. After the reaction completion, ammonium chloride solution, ethyl acetate was added to the reaction mass, stirred and layers were separated. Hydrochloric acid (250 ml) was added to the separated organic layer at below 10°C. Organic layer was separated, washed with aqueous sodium bicarbonate followed by sodium chloride solution and then distilled off under reduced pressure at below 50°C to get the title compound.

Example-2:
Preparation of diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecane dioate:
p-toluene sulfonyl methyl isocyanide (370 g), tetrabutylammonium iodide (140 g) followed by ethyl 7-bromo-2,2-dimethylheptanoate (1 Kg) was added to a mixture of toluene (5 L), dimethylformamide (5 L) and sodium hydride (182 g) at 0-5°C and stirred. After reaction completion, the reaction mass was quenched with ice-water at below 10°C. Organic and aqueous layer were separated, organic layer washed with water followed by sodium chloride solution. Organic layer containing title compound used directly in next step without any purification.
Example-3:
Preparation of diethyl-2,2,14,14-tetramethyl-8-oxopentadecanedioate:
Hydrochloric acid (1 L) was added to a organic layer containing diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecane dioate at 0-5°C and stirred for 2 hours. After reaction completion, the reaction mass was filtered and the toluene layer was separated from filtrate, washed with aqueous sodium bicarbonate, sodium chloride solution and dried with sodium sulfate. Organic layer containing the title compound used in next step without any purification.

Example 4:
Preparation of bempedoic acid:
To the organic layer containing diethyl-2,2,14,14-tetramethyl-8-oxopentadecane dioate obtained in example-3, ethanol (3.5 L), sodium hydroxide solution (160 grams in 160 ml of water), sodiumborohydride (40 g) were added at 25-35°C and stirred for 2 hrs. After reaction completion, sodium hydroxide solution (600 grams dissolved in 600 ml water) was added to the reaction mass and stirred. The reaction mass was heated to 55-60°C and stirred for 6 hrs. After reaction completion, the reaction mass cooled to 25-35°C, water (4 L) was added and stirred. Organic and aqueous layers were separated, aqueous layer acidified with hydrochloric acid and extracted with methyl tertiary butyl ether. MTBE layer was distilled under reduced pressure at below 40°C and acetonitrile was added to the obtained residue, heated to 65-70°C and stirred for 1.5 hrs. The reaction mass cooled to 20-30°C and stirred for 3 hrs. The obtained solid was filtered, washed with acetonitrile and dried to get the title compound.
Yield: 650 g. Purity by HPLC: 99%;
The PXRD pattern is shown in Figure-1.

Example 5:
Purification of bempedoic acid:
A mixture of bempedoic acid (1Kg), ethylacetate (2 L) and acetone (2 L) was heated to 45-50°C and stirred for an hour at the same temperature. The reaction mass was cooled to 25-30°C, stirred for an hour, further cooled to 10-15°C and stirred for an hour. The solid obtained was filtered, washed with ethyl acetate and dried to get the pure title compound.
Yield: 694 g. Purity: 99.85%
The PXRD pattern is shown in Figure-1.

Example 6:
Purification of bempedoic acid:
A mixture of bempedoic acid (1Kg) and ethyl acetate (4 L) was heated to 50-55°C and stirred for 30 mins at the same temperature. The reaction mass was cooled to 0-5°C and stirred for 2 hours. The solid obtained was filtered, washed with ethyl acetate and dried to get the pure title compound.
Yield: 690 g. Purity: 99.2%

Example 7:
One-pot preparation of bempedoic acid:
p-toluene sulfonyl methyl isocyanide (370 g), tetrabutylammonium iodide (140 g) followed by ethyl 7-bromo-2,2-dimethylheptanoate (1 Kg) was added to a mixture of toluene (5 L), dimethylformamide (5 L) and sodium hydride (182 g) at 0-5°C and stirred. After reaction completion, the reaction mass was quenched with ice-water at below 10°C. Organic and aqueous layer were separated, organic layer washed with water followed by sodium chloride solution. Hydrochloric acid (1 L) was added to a organic layer at 0-5°C and stirred for 2 hours. After reaction completion, the reaction mass was filtered and the toluene layer was separated from filtrate, washed with aqueous sodium bicarbonate, sodium chloride solution and dried with sodium sulfate.
Ethanol (3.5 L), sodium hydroxide solution (160 grams in 160 ml of water), sodiumborohydride (40 g) were added to the organic layer at 25-35°C and stirred for 2 hrs. After reaction completion, sodium hydroxide solution (600 grams dissolved in 600 ml water) was added to the reaction mass and stirred. The reaction mass was heated to 55-60°C and stirred for 6 hrs. After reaction completion, the reaction mass cooled to 25-35°C, water (4 L) was added and stirred. Organic and aqueous layers were separated, aqueous layer acidified with hydrochloric acid and extracted with methyl tertiary butyl ether. MTBE layer was distilled under reduced pressure at below 40°C and acetonitrile was added to the obtained residue, heated to 65-70°C and stirred for 1.5 hrs. The reaction mass cooled to 20-30°C and stirred for 3 hrs. The obtained solid was filtered, washed with acetonitrile and dried to get the title compound.
Yield: 623 g. Purity by HPLC: 99%
,CLAIMS:1. A process for the preparation of bempedoic acid of formula I,

Formula I
which comprises;
a) reacting 1,5-dibromopentane of formula II

Formula II
with alkyl isobutyrate compound of formula III

Formula III
wherein R is C1-C6 alkyl; in presence of a base in a suitable solvent to provide alkyl 7-bromo-2,2-dimethylheptanoate of formula IV, wherein R is C1-C6 alkyl;

Formula IV
b) reacting the compound of formula IV with p-toluene sulfonyl methyl isocyanide in presence of a base and a catalyst in a suitable solvent to provide compound of formula V, wherein R is C1-C6 alkyl;

Formula V
c) reacting the compound of formula V with a suitable acid in a suitable solvent to provide keto compound of formula VI, wherein R is C1-C6 alkyl;

Formula VI
d) reducing the keto compound of formula VI with a suitable reducing agent in presence of a base in a suitable solvent to provide the compound of formula VII, wherein R is C1-C6 alkyl,

Formula VII
e) hydrolyzing the compound of formula VII with a suitable base or acid in a suitable solvent to provide the bempedoic acid of formula I.

2. The process as claimed in claim 1, wherein the compound of formula V, the compound of formula VI and the compound of formula VII is not isolated.

3. The process as claimed in claim 1, wherein, in step a) the base is lithium diisopropylamide and the solvent is selected from ethers, aliphatic hydrocarbons or mixtures thereof; in step b) the base is sodium hydride; the catalyst is tetrabutylammonium halide; and the solvent is selected from aromatic hydrocarbons, amides, sulfoxides, ethers, aliphatic hydrocarbons, ketones, or mixtures thereof; in step c) the suitable acid is selected from acetic acid, hydrochloric acid or sulphuric acid; and the solvent is selected from aromatic hydrocarbons; in step d) the suitable reducing agent is selected from sodium borohydride, sodium triacetoxyborohydride, sodiumcyano borohydride and potassium borohydride; the suitable solvent is selected from water, alcohols, aromatic hydrocarbons, ethers and mixtures thereof; the suitable base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate; in step e) the suitable base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium methoxide, sodium t-butoxide; the suitable acid is selected from aqueous hydrochloric acid or sulphuric acid; and the solvent is selected from water, alcohols, aromatic hydrocarbons, ethers and mixtures thereof.

4. A process for the preparation of bempedoic acid of formula I, which comprise of reducing the keto compound of formula VI with a suitable reducing agent in a suitable solvent, followed by treating with a suitable base to provide bempedoic acid of formula I.

5. The process as claimed in claim 4, wherein the suitable reducing agent is selected from sodium borohydride, sodium triacetoxyborohydride, sodiumcyano borohydride and potassium borohydride; the suitable solvent is water, alcohols, aromatic hydrocarbons, ethers and mixtures thereof; the suitable base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium methoxide and sodium t-butoxide.

6. A process for the preparation of bempedoic acid, which comprise of reacting the compound of formula V with a suitable acid to provide keto compound of formula VI, wherein the said reaction is carried out in presence of aromatic hydrocarbon solvent.

7. The process as claimed in claim 6, wherein the suitable acid is selected from acetic acid, sulphuric acid and hydrochloric acid; and the aromatic hydrocarbon solvent is selected from toluene, xylene, benzene and mixtures thereof.

8. A process for the purification of bempedoic acid compound of formula I, which comprise of crystallizing bempedoic acid from a suitable solvent selected from nitriles, ketones, ethers, esters and mixtures thereof.

9. The process as claimed in claim 8, wherein the suitable solvent is selected from acetone, ethyl acetate, acetonitrile, methyltertiarybutyl ether and mixtures thereof.

10. Crystalline form of bempedoic acid characterized by its powder X-ray diffraction having one or more peaks at about 5.14, 10.30, 15.46, 17.24, 17.52, 17.89, 18.21, 18.69, 19.46, 20.33, 20.67, 21.78, 22.55, 23.50 and 27.49 ± 0.2 degrees 2?.

Dated this ____ day of June 2020.

Nandepu Venkateswara Rao
Managing Director
Metrochem API Pvt Ltd.